Disruption of the Autism-Associated Pcdh9 Gene Leads to Transcriptional Alterations, Synapse Overgrowth, and Defective Network Activity in the CA1

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Abstract
Protocadherins, a family of adhesion molecules with a crucial role in cell–cell interactions, have emerged as key players in neurodevelopmental and psychiatric disorders. In particular, growing evidence links genetic alterations in the protocadherin 9 ( PCDH9 ) gene with autism spectrum disorder and major depressive disorder. Furthermore, Pcdh9 deletion induces neuronal defects in the mouse somatosensory cortex, accompanied by sensorimotor and memory impairment. However, the synaptic and molecular mechanisms of PCDH9 in the brain remain largely unknown, particularly concerning its impact on brain pathology. To address this question, we conducted a comprehensive investigation of PCDH9’s role in the male mouse hippocampus at the ultrastructural, biochemical, transcriptomic, electrophysiological, and network levels. We show that PCDH9 mainly localizes at glutamatergic synapses and its expression peaks in the first week after birth, a crucial time window for synaptogenesis. Strikingly, Pcdh9 KO neurons exhibit oversized presynaptic terminal and postsynaptic density in the CA1. Synapse overgrowth is sustained by the widespread upregulation of synaptic genes, as revealed by single-nucleus RNA-seq (snRNA-seq), and the dysregulation of key drivers of synapse morphogenesis, including the SHANK2/CORTACTIN pathway. At the functional level, these structural and transcriptional abnormalities result in increased excitatory postsynaptic currents (mEPSC) and reduced network activity in the CA1 of Pcdh9 KO mice. In conclusion, our work uncovers Pcdh9 ’s pivotal role in shaping the morphology and function of CA1 excitatory synapses, thereby modulating glutamatergic transmission within hippocampal circuits.
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  • Fondazione Cariplo (2019-3438)

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